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Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial Torsten Sandberg, Gunilla Skoog, Anna Bornefalk Hermansson, Gunnar Kahlmeter, Nils Kuylenstierna, Anders Lannergård, Gisela Otto, Bo Settergren, Gunilla Stridh Ekman

Summary Background Acute pyelonephritis is a common infection in adult women, but there is a paucity of controlled trials of its treatment and the optimum duration of antibiotic treatment has not been properly defined. We compared the efficacy of ciprofloxacin for 7 days and 14 days in women with community-acquired acute pyelonephritis. Methods In a prospective, non-inferiority trial undertaken at 21 centres of infectious diseases in Sweden, women (aged ≥18 years) who were not pregnant and had a presumptive diagnosis of acute pyelonephritis were randomly assigned to oral treatment with ciprofloxacin 500 mg twice daily for 7 days or 14 days. The first week was open label. A computer-generated randomisation list in block sizes of two was used for treatment allocation in a 1:1 ratio. The study was double-blind and placebo-controlled during the second week of treatment, which was either continuation of ciprofloxacin 500 mg or placebo tablets twice daily according to the randomisation code. Patients, carers, site investigators, and trial coordinating centre staff were masked to group assignment. The primary endpoint was the clinical and bacteriological outcome 10–14 days after completion of treatment with active drug. Analysis was by per protocol. This trial is registered with EudraCT, number 2005-004992-39, and ClinicalTrials.gov, number ISRCTN73338924. Findings 126 of 248 patients were randomly assigned to 7 days and 122 to 14 days of ciprofloxacin. 73 and 83 patients, respectively, were analysed. Short-term clinical cure occurred in 71 (97%) patients treated with ciprofloxacin for 7 days and 80 (96%) treated for 14 days (difference –0·9%; 90% CI –6·5 to 4·8; p=0·004; non-inferiority test). Cumulative efficacy at long-term follow-up was 93% in each group (68 of 73 vs 78 of 84; –0·3%; –7·4 to 7·2; p=0·015). Both regimens were well tolerated. Two patients discontinued ciprofloxacin because of myalgia with 7 days of treatment and itching exanthema with 14 days. Four (5%) of 86 patients assigned to 7 days of treatment who complied with study criteria and six (6%) of 93 assigned to 14 days reported an adverse event after the first week of treatment that was possibly or probably related to the study drug. In those assigned to 7 days, no patient had mucosal candida infection after the first week versus five treated for 14 days (p=0·036). Interpretation Our results show that acute pyelonephritis in women, including older women and those with a more severe infection, can be treated successfully and safely with oral ciprofloxacin for 7 days. Short courses of antibiotics should be favoured in an era of increasing resistance. Funding Swedish Strategic Programme against Antibiotic Resistance (Strama).

Introduction The antibiotic resistance of Enterobacteriaceae, the most common cause of urinary tract infections, has increased worldwide.1,2 The treatment options are becoming increasingly few and thus are a public health concern. An important way to tackle antibiotic resistance is to reduce antibiotic consumption—eg, by shortening the duration of treatment.3,4 Controlled, randomised studies are needed to define the minimum treatment regimens for common infectious diseases.3,4 Acute pyelonephritis is a common and potentially serious infection affecting women of all ages. Few controlled trials have been done to assess the optimum duration of treatment for this infection.5 A 2 week regimen of trimethoprim-sulfamethoxazole (co-trimoxazole)6 or a fluoroquinolone7 resulted in high rates of clinical and

bacteriological cure. Therefore, 14 days of antimicrobial treatment is thought to be appropriate. In young women with mild, uncomplicated pyelonephritis who were managed on an outpatient basis, ciprofloxacin for 7 days was more efficacious than 14 days of co-trimoxazole.8 This finding was, however, ascribed to a higher frequency of resistant bacteria in women treated with co-trimoxazole.8 In our investigator-initiated study, adult women with community-acquired acute pyelonephritis were treated with ciprofloxacin for 7 days or 14 days. The primary objective was to compare the short-term clinical and bacteriological efficacy and safety of the two regimens. Secondary aims were to assess the long-term cumulative efficacy and the consequences of not treating patients who had asymptomatic bacteriuria at short-term followup after completion of treatment.

www.thelancet.com Published online June 21, 2012 http://dx.doi.org/10.1016/S0140-6736(12)60608-4

Published Online June 21, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)60608-4 See Online/Comment http://dx.doi.org/10.1016/ S0140-6736(12)60770-3 Department of Infectious Diseases, Sahlgrenska University Hospital, Göteborg, Sweden (T Sandberg MD); Swedish Institute for Infectious Disease Control, Solna, Sweden (G Skoog MSc, G Stridh Ekman MSc); Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala, Sweden (A Bornefalk Hermansson PhD); Department of Clinical Microbiology, Central Hospital, Växjö, Sweden (Prof G Kahlmeter MD); Department of Infectious Diseases, Central Hospital, Falun, Sweden (N Kuylenstierna MD); Department of Infectious Diseases, Uppsala University, Uppsala, Sweden (A Lannergård MD); Department of Infectious Diseases, Skåne University Hospital, Lund, Sweden (G Otto MD); and Department of Infectious Diseases, Central Hospital, Kristianstad, Sweden (B Settergren MD) Correspondence to: Dr Torsten Sandberg, Department of Infectious Diseases, Sahlgrenska University Hospital, SE-416 85 Göteborg, Sweden [email protected]

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Methods Study design and patients This study was a prospective, randomised, double-blind, non-inferiority trial with parallel groups. It was undertaken at 21 centres of infectious diseases in Sweden. Women aged 18 years or older with a presumptive diagnosis of community-acquired acute pyelonephritis were recruited to the study. Eligible patients had fever of at least 38·0°C (measured at home or in the emergency department) and at least one symptom or sign relating to the urinary tract such as flank pain, costovertebral angle tenderness, dysuria, urgency, or frequency. A detailed medical history was obtained and a physical examination was done to assess eligibility. Symptoms and signs, a history of urinary tract infections and genitourinary disorders, concomitant diseases, and current medication were recorded. The infection was classified as sporadic (one previous episode of urinary tract infection during the past 6 months or no more than two during the past 12 months) or recurrent infection. The current episode was also classified as uncomplicated or complicated (diabetes mellitus or known structural or functional abnormalities of the urinary tract that might predispose to infections). The patients were initially hospitalised or directly managed on an outpatient basis at the discretion of the attending physician. Patients were excluded from enrolment for any of the following reasons: pregnancy or lactation; inadequate contraception for women of childbearing age; known hypersensitivity to fluoroquinolones; systemic antibiotic treatment within the preceding 72 h; presence of an indwelling urinary catheter or clean intermittent catheterisation of the bladder; estimated creatinine clearance of less than 0·5 mL/s; convulsive disease; concomitant treatment with antacids, sucralfate, zinc, or theophylline; or previous inclusion in this study. The Medical Products Agency, Uppsala, Sweden, and the ethical review committee at the University of Gothenburg approved the study protocol. The study was done in accordance with the ethical principles of the Declaration of Helsinki and the Guidelines for Good Clinical Practice. Written informed consent to participate in the trial was obtained from all patients.

Randomisation and masking

For more on disc diffusion for susceptibility testing see http://www.srga.org/

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Patients were allocated to oral treatment in a 1:1 ratio. For comparison of the efficacy of different periods of antibiotic treatment, identical daily doses were used. The first week of treatment was open-label and all patients were given oral ciprofloxacin 500 mg twice daily. At the start of treatment, the investigator could administer discretionary ciprofloxacin 400 mg intravenously. The second week was double-blind and placebo-controlled and treatment was continued with either ciprofloxacin 500 mg or placebo tablets twice daily according to the randomisation code. Apoteket Produktion and Laboratorier AB (Stockholm, Sweden) computer-generated the allocation sequence for

randomisation with block sizes of two for each study site. Trial drugs were packaged and assigned a randomisation number by Apoteket Produktion and Laboratorier AB and delivered to each participating centre. Enrolled patients thus were given by the investigator two blister packets of study medication in numerical order, one containing ciprofloxacin for the first week of treatment and another containing either ciprofloxacin or placebo tablets for the second week. Ciprofloxacin 500 mg and placebo tablets were identical with respect to shape, colour, taste, and odour and were provided by Bayer AB, Solna, Sweden. Patients, carers, site investigators, and trial coordinating centre staff were masked to group assignment.

Procedures One or two clinical investigators were involved at each participating centre. Investigators and a coordinating committee met before and twice during the study to discuss all procedures. Members of the coordinating committee convened regularly to discuss any problems or inconsistencies that arose during the trial. We obtained a voided midstream urine sample for culture and screening for the presence of nitrite and granulocyte esterase as an indicator of pyuria, blood specimens for culture and measurement of C-reactive protein (CRP), and creatinine after randomisation but before the start of antibiotic treatment. Women of childbearing age were given a pregnancy test. Early follow-up was scheduled 10–14 days after the end of treatment with ciprofloxacin. Since the second week of treatment was masked, each patient had to be seen at two early visits—ie, days 17–21 and 24–28. For patients given ciprofloxacin for 7 days, results from days 17–21 were used and, for those who were given a 14 day course, data from days 24–28 were used. Long-term outcome was assessed with a late follow-up visit on days 42–63. Clinical assessments with focus on genitourinary symptoms and enquiry about further episodes of systemic antibiotic treatment were done at each visit. Repeat urine cultures and blood samples for measurement of serum CRP and serum creatinine concentrations were also obtained. Compliance with treatment was ascertained through enquiry and counting the unused tablets of the trial drug at the first follow-up visit. Patients were encouraged to consult the outpatient clinic if symptoms of urinary tract infection recurred during follow-up and all procedures were repeated. The urine was cultured with standard microbiological methods by use of the calibrated loop technique at local laboratories. Clinically significant growth was defined as at least 10³ colony-forming units (cfu) per mL of urine of Escherichia coli or Staphylococcus saprophyticus and at least 10⁴ cfu per mL of other uropathogens. Urine samples containing more than two bacterial species were judged to be contaminated. Susceptibility testing against ciprofloxacin was done with disc diffusion and minimum inhibitory concentration (MIC; E-test,

www.thelancet.com Published online June 21, 2012 http://dx.doi.org/10.1016/S0140-6736(12)60608-4

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bioMerieux, Lyon, France) and breakpoints from the European Committee on Antimicrobial Susceptibility Testing. The breakpoints used for Enterobacteriaceae and Pseudomonas aeruginosa were defined as susceptible when less or equal to 0·5 mg/L and resistant when greater than 1·0 mg/L and for S saprophyticus susceptible was defined as less or equal to 1 mg/L and resistant when greater than 1 mg/L. Two sets of blood cultures, obtained before treatment, were incubated both aerobically and anaerobically. All isolates were stored for ascertaining MIC at a reference laboratory. Patients were randomly assigned before a definite diagnosis of acute pyelonephritis was established. Thus, patients were excluded from the study if they did not have acute pyelonephritis; if a pretreatment urine culture was missing, showed non-significant bacteriuria, or grew more than two bacterial species; if isolated bacteria were resistant or showed reduced susceptibility to ciprofloxacin; or if other antibiotics were given with ciprofloxacin when treatment was started. Patients were not eligible for per-protocol analysis for the following reasons: no follow-up visit; systemic treatment with other antimicrobial drugs up to day 28 (visit three); or missing more than one dose of the study drug during the first week of treatment or more than two doses during the whole treatment period. Clinical cure was defined as complete resolution of symptoms during treatment with no recurrence of symptoms or signs of urinary tract infection during follow-up. Discontinuation of treatment because of worsened or persistent symptoms or the occurrence of adverse events was designated a clinical failure. The clinical failure or recurrence of symptoms of urinary tract infection (acute cystitis or acute pyelonephritis) during follow-up was judged to be a definite endpoint for participation in the study. Bacteriological cure was defined as eradication of the infecting strain with no recurrence of bacteriuria (